2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Learning-Disabilities

There is evidence for the existence of two classes of sigma binding sites, termed "site 1" and "site 2", that are distinct from opioid and PCP receptors. Sigma receptor ligands may be useful in the treatment of schizophrenia, since they improve not only positive but also negative symptoms with little extrapyramidal side effects in animal models. In addition, recent experiments have demonstrated that sigma receptor ligands attenuate the motor suppression and colonic motor disturbances seen under mentally stressful situations, stimulate the central cholinergic function thereby ameliorating impairment of learning and memory, and protect cerebral neurons against cerebral ischemic insult. The present review describes the neuropharmacological effects of sigma receptor ligands, especially anxiolytic (anti-stress) effects, ameliorating effects on impairment of learning and memory, and neuroprotective effects.

Topics: Animals; Antipsychotic Agents; Anxiety; Brain Ischemia; Cinnamates; Cyclopropanes; Humans; Learning Disabilities; Memory Disorders; Phenazocine; Phencyclidine; Receptors, sigma

The sigma1 (sigma1) receptor cDNA was recently cloned in several animal species, including the mouse. In order to firmly establish the implication of sigma1 receptors in memory, a phosphorothioate-modified antisense oligodeoxynucleotide (aODN) targeting the sigma1 receptor mRNA and a mismatched analog (mODN) were administered intracerebroventricularly for 3 days in mice. Scatchard analyses of in vitro (+)-[3H]SKF-10,047 binding to sigma1 sites showed that Bmax values were significantly decreased in the hippocampus (-58.5%) and cortex (-38.1%), but not in the cerebellum, of aODN treated mice, as compared to saline- or mODN-treated animals. In vivo binding levels were also significantly decreased after aODN treatment in the hippocampus and cortex but not in the cerebellum. The anti-amnesic effects of the selective sigma1 agonists PRE-084 or SA4503 were evaluated against the learning impairments induced by dizocilpine or scopolamine, respectively, using spontaneous alternation behavior and passive avoidance task. The anti-amnesic effects of PRE-084 or SA4503, observed after saline- or mODN-treatment, were blocked after aODN administration. These observations bring a molecular basis to the modulatory role of sigma1 receptors in memory processes.

Topics: Amnesia; Animals; Brain; Dizocilpine Maleate; Excitatory Amino Acid Agonists; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Mice; Morpholines; Nootropic Agents; Oligonucleotides, Antisense; Phenazocine; Piperazines; Receptors, sigma

1. The sigma(1) (sigma(1)) receptor cDNA was cloned in several animal species. Molecular tools are now available to identify its endogenous effectors, such as neuroactive steroids, and to establish its precise physiological role. In particular, the sigma(1) receptor is involved in memory processes, as observed in pharmacological and pathological rodent models of amnesia. 2. In order to establish the involvement of sigma(1) receptors in memory, a 16-mer oligodeoxynucleotide antisense to the sigma(1) receptor cDNA (aODN), and its mismatched control (mODN) were prepared and centrally administered into the mouse brain. The anti-amnesic effects induced by the selective sigma(1) agonist PRE-084 and the steroid dehydroepiandrosterone (DHEA) sulphate or pregnenolone sulphate were examined in ODN-treated animals. 3. The aODN treatment failed to affect the dissociation constant (K(d)) but significantly decreased the number of sigma(1) sites (B(max)) labelled with [(3)H]-(+)-SKF-10,047 in the hippocampus and cortex. In these structures, the in vivo binding levels were also diminished, according to the dose and number of injections, as compared with control animals injected with saline or mODN. 4. Cannulation and injections failed to affect the open-field behaviour of the animals. However, the anti-amnesic effects of PRE-084 and DHEA sulphate against the dizocilpine-induced impairments were blocked after aODN treatment in the short- and long-term memory tests. The anti-amnesic effects of pregnenolone sulphate remained unchanged. 5. These observations bring a molecular basis to the modulatory role of sigma(1) receptors in memory, and reveal that the anti-amnesic action of neuroactive steroids may not similarly involve an interaction with sigma(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Behavior, Animal; Binding Sites; Blotting, Western; Brain; Cerebral Cortex; Dehydroepiandrosterone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; In Vitro Techniques; Learning Disabilities; Male; Maze Learning; Memory; Mice; Morpholines; Oligonucleotides, Antisense; Phenazocine; Pregnenolone; Receptors, sigma; Sigma-1 Receptor